thromboxane-a2 and tetramethylpyrazine

Aberrant activation of platelets has a critical role in thrombotic vascular events, including atherosclerosis, arterial thrombosis and myocardial infarction. The process of platelet activation is associated with multiple intracellular signaling pathways, including the phosphoinositide 3‑kinase/AKT serine/threonine kinase (Akt) pathway. The well‑known medicinal herb Rhizoma Ligusticum Wallichii (RLW) has long been used in China to clinically treat various cardiovascular disorders. As the most pharmacologically active component of RLW, ligustrazine has been demonstrated to possess a potent antiplatelet activity. However, the precise mechanisms mediating the bioactivities of ligustrazine have not been thoroughly elucidated. The present study evaluated the effects of ligustrazine hydrochloride (LH; the clinical‑grade form of ligustrazine) on platelet activation and investigated the underlying molecular mechanisms. In vitro and ex vivo platelet activation models were used, established by stimulating rat platelet‑rich plasma either with the platelet activator adenosine diphosphate (ADP) or with the specific Akt pathway activator insulin‑like growth factor‑1 (IGF‑1). The results demonstrated that treatment with LH significantly and dose‑dependently inhibited ADP‑induced platelet aggregation, in addition to thromboxane A2 (TXA2) secretion and intracellular Ca2+ mobilization in platelets, in vitro and ex vivo. In addition, LH markedly suppressed ADP‑induced Akt phosphorylation in vitro and ex vivo. Furthermore, LH markedly inhibited IGF‑1‑induced Akt phosphorylation, platelet aggregation, TXA2 formation and Ca2+ mobilization in vitro. Finally, LH was able to reverse adrenaline‑induced shortening of bleeding time. Taken together, these results suggested that ligustrazine possesses a broad range of antiplatelet activities without apparent hemorrhagic side-effects, and suppression of Akt signaling may be one of the mechanisms by which ligustrazine exerts its antiplatelet activities.

Topics: Animals; Calcium; Hemorrhage; Insulin-Like Growth Factor I; Male; Phosphorylation; Platelet Activation; Platelet Aggregation; Proto-Oncogene Proteins c-akt; Pyrazines; Rats, Sprague-Dawley; Signal Transduction; Thromboxane A2

To explore the effects of ligustrazine on proteinuria, urinary TxB2 (metabolism of thromboxane A2, TxA2) and 6-keto-PGF1alpha (metabolism of prostacyclines I2, PG I2), glomerular inducible nitric oxide(NO) synthase (iNOS) mRNA, urinary NO3-/NO2- (decomposing products of NO) and pathological changes in rats with passive Heymann nephritis (PHN).. A rat PHN model was induced by intravenous injection of rabbit anti-rat renal tubular antigen (Tub-Ag) antiserum, and ligustrazine was given intraperitoneally into PHN rats every 2 days for 1-5 weeks. Then, proteinuria, urinary TxB2 and 6-keto-PGF1alpha, glomerular iNOS mRNA, and urinary NO3-/NO2- were measured by sulfosalicylic acid, radioimmunoassay (RIA), Northern blot and nitric acid reductase methods, respectively. Moreover, the damage to the renal tissue of the rats was observed under light and electron microscopy and immunofluorescence (IF).. The urinary TxB2 in PHN rats was significantly higher than that in control rats, but the PHN rats treated with ligustrazine had significantly less proteinuria, urinary TxB2 and tissue lesions, and more urinary 6-keto-PGF(1alpha), glomerular iNOS mRNA and urinary NO2-/NO3- than the PHN rats without the administration of ligustrazine.. These data indicate that ligustrazine has inhibitory roles on the glomerular injury of PHN rats, which may associate with modulating the balance of TxA2-PGI2 and elevating synthesis of NO to a certain extent.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Female; Fluorescent Antibody Technique, Direct; Glomerular Basement Membrane; Glomerulonephritis; Immunoglobulin G; Kidney Glomerulus; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type II; Nitrites; Proteinuria; Pyrazines; Rats; RNA, Messenger; Thromboxane A2

Pretreatment with tetramethylpyrazine (TMP, 12 mg/kg/day), a drug originally derived from the rhizomes of Ligusticum wallichii, significantly reduced the incidence of ischemia-induced ventricular tachycardia (VT) and fibrillation (VF) from 100% and 50% of control hearts to 41% (p < 0.05) and 0% (p < 0.05), respectively, in the ischemic rat heart. TMP also diminished the incidence of reperfusion-induced VT and VF from 100% and 100% of control hearts to 33% (p < 0.05) and 41% (p < 0.05), respectively. Pretreatment with TMP produced a slight, but significant increase of 6-keto-PGF1 alpha and a decrease of TXB2 production during aerobic perfusion. Ischemia and reperfusion markedly increased the release of 6-keto-PGF1 alpha and TXB2. Pretreatment with TMP significantly enhanced the release of 6-keto-PGF1 alpha and diminished TXB2 outflow following left coronary artery occlusion and reperfusion.

Topics: Animals; Arrhythmias, Cardiac; Epoprostenol; Heart; Male; Myocardial Ischemia; Pyrazines; Rats; Rats, Sprague-Dawley; Thromboxane A2

We examined the effect on 6-Keto-PGF1a and TXB2 (the stable metabolites of PGI2 and TXA2) outflow of pretreatment with tetramethylpyrazine in the hypoxic isolated rat heart. In control hearts, 6-Keto-PGF1a was increased from 185 +/- 46 pg/ml of baseline value to 335 +/- 76 pg/ml after 2 min of hypoxia and TXB2 increased from 136 +/- 28 pg/ml of baseline value to 230 +/- 43 pg/ml at 20 min of hypoxia and 252 +/- 32 pg/ml after 5 min of reoxygenation. Pretreatment with tetramethylpyrazine increased the 6-Keto-PGF1a concentration to 266 +/- 51 pg/ml (143% of control heart), 471 +/- 89 pg/ml (150% of control heart) and 332 +/- 47 pg/ml (195% of control heart) at 15 min of normoxia, 2 min of hypoxia and 5 min of reoxygenation, respectively (p < 0.05 vs control). On the other hand, tetramethylpyrazine diminished the release of TXB2 to 78 +/- 21 pg/ml (174% of control heart), 160 +/- 30 pg/ml (144% of control heart), and 196 +/- 23 pg/ml (128% of control heart) at 15 min of normoxia, 20 min of hypoxia and 5 min of reoxygenation, respectively (p < 0.05 vs control). These data show that pretreatment with tetramethylpyrazine enhances PGI2 outflow and attenuates release of TXA2 in the rat heart during normoxia, hypoxia and reoxygenation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Coronary Circulation; Epoprostenol; Heart; Hypoxia; In Vitro Techniques; Male; Myocardium; Perfusion; Platelet Aggregation Inhibitors; Pyrazines; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane B2; Time Factors; Vasodilator Agents

Topics: Albuminuria; Animals; Benzofurans; beta 2-Microglobulin; Cyclosporine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Immunosuppressive Agents; Kidney; Organ Size; Pancreas Transplantation; Pyrazines; Rats; Rats, Wistar; Thromboxane A2; Thromboxane-A Synthase; Transplantation, Isogeneic

We investigated the release of PGI2 and TXA2 by measuring their stable metabolites of 6-keto-PGF1a and TXB2 in the perfusate in the isolated rat heart after pretreatment with tetramethylpyrazine (TMP). Pretreatment with TMP (12 mg/kg, i.p.) 7 days before preparation produced a significant elevation of 6-keto-PGF1a from 2.30 +/- 0.65 ng/min/g of untreated controls to 3.8 +/- 0.77 ng/mir/g (p < 0.05). Pretreatment with TMP also decreased TXB2 release (p < 0.05 versus control).

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Heart; In Vitro Techniques; Male; Myocardium; Pyrazines; Rats; Rats, Sprague-Dawley; Reference Values; Thromboxane A2; Vasodilator Agents

The clinical efficiency and mechanism of traditional Chinese medicinal herb Salvia Miltiorrhizae Bge (SMB) and Ligustrazine (L) on pregnancy induced hypertension (PIH) were studied in 30 patients. Before and after the administration of SMB and L, the following parameters: mean arterial pressure (MAP), proteinuria, levels of Thromboxane A2 (TXA2) and Prostacyclin (PGI2) were observed. TXA2 and PGI2 were measured by their stable hydration products Thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by an established radioimmunoassay. The results of treatment were compared with the base line values and showed as follows: MAP and proteinuria decreased significantly (P < 0.05); no marked difference existed in TXB2; the level of 6-keto-PGF1 alpha increased significantly (P < 0.05); the rate of TXB2/6-keto-PGF1 alpha decreased significantly (P < 0.05). The results suggested that SMB and L can invigorate blood circulation by decreasing vasoconstriction.

Topics: Adult; Drugs, Chinese Herbal; Epoprostenol; Female; Humans; Plant Extracts; Pre-Eclampsia; Pregnancy; Pyrazines; Salvia miltiorrhiza; Thromboxane A2

Topics: Animals; Fibrinolytic Agents; Male; Medicine, Chinese Traditional; Medicine, East Asian Traditional; Plant Extracts; Plants, Medicinal; Pyrazines; Rabbits; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes